Hsp90 proteins are implicated in stabilizing protein conformations, maintaining the function of many cell-signaling proteins, and ATPase activity. Hsp90 activity is also required for the proper folding, stabilization, activation, and localization of oncoproteins involved in tumor progression. The N-terminus ATP binding domain is responsible for the ATPase activity of this protein: this adenine nucleotide binding pocket is highly conserved among all Hsp90 proteins from bacteria to mammals but is not present in other chaperones.
Hsp90 protein has emerged as an important target in cancer treatment, as many Hsp90 client proteins themselves were identified as targets for cancer therapies. The exemplary Hsp90 client proteins that are associated with cancer include HER2 (breast cancer), Raf-1/mutant BRAF (melanoma), Mutant EGFR (non-small cell lung cancer, glioblastoma), c-Kit (GIST), c-Met (gastric, lung, glioblastoma), HIF-1α (renal cancer), Zap70 (chronic lymphocytic leukemia), Bcr-Abl (chronic myelogenous leukemia), mBcr-Abl (chronic myelogenous leukemia), Flt-3 (acute myeloid leukemia), IGF-1R/Akt (myeloma), NMP-ALK (lymphoma), and Akt (small cell lung cancer). Overexpression of mutated Hsp90 client or amplification of its clients, such as HER2, leads to the increased dependency of tumor cells on Hsp90 chaperone function. Accordingly, Hsp90 provides a compelling target for treating different classes of tumors.
Increased levels of Hsp90 have also been implicated in neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, and tauopathies. Tauopathies are neurodegenerative diseases characterized by tau protein abnormalities, which then result in the accumulation of hyperphosphorylated and aggregated tau protein. It has been proposed that hyperphosphorylated tau in Alzheimer's disease is a pathogenic process caused by aberrant activation of kinases, particularly cdk5 and GSK β3. Studies have shown that Hsp90 stabilizes p35, an activator of cdk5, leading to increased tau phosphorylation. It has also been shown that Hsp90 inhibition activates heat shock factor 1 (HSF1), which in turn increases the expression of Hsp70. Increased expression of Hsp70 promotes tau solubility and binding to microtubules, inhibits Aβ peptide aggregation, and enhances Aβ peptide degradation.
Hsp90 has also emerged as a target for treating viral, fungal, and bacterial infections. For example, an Hsp90 inhibitor (geldanamycin) has been shown to delay the growth of influenza virus in cell culture.
Other viruses that rely on Hsp90 dependent processes include those belonging to the families: Herpesviridae (e.g., herpes simplex virus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barr virus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus), Reoviridae (e.g., rotavirus), Birnaviridae (e.g., infectious bursal disease virus), picornaviridae (e.g., poliovirus, rhinovirus, or coxsackievirus), flaviviridae (e.g., hepatitis C virus or dengue virus), arenaviridae (e.g., lymphocytic choriomeningitis virus), Hepeviridae (e.g., Hepatitis E virus), Rhabdoviridae (e.g., vesicular stomatitis virus), Paramoxyviridae (e.g., human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus), Bunyaviridae (e.g., La Crosse virus), Orthomoxyviridae (e.g., influenza A virus), Filoviridae (e.g., Ebola virus), Retroviridae (e.g., HTLV1 or HIV1), and Hepadnaviridae (e.g., hepatitis B virus). Hsp90 inhibitors have also been used in vivo for the treatment of fungal infectious diseases, e.g., treatment of Candida albicans, Aspergillus fumigates, or Pneumocystis jiroveci. Moreover, Hsp90 inhibitors are also useful in the treatment of bacterial infections, e.g., mycobacteria, anthrax, or bacterial pneumonia.
In view of the above, inhibitors of Hsp90 represent beneficial therapeutics for the treatment of disorders, e.g., cancer, neurodegenerative diseases, and infectious diseases.